Urinary tract infections are a major problem in medicine. Every part of the urinary tract may be affected. The most common forms of the illness are: cystitis, the urethral syndrome, pyelitis, and pyelonephritis. A tendency for recurrence and chronic progression is characteristic of urinary tract infections. The disease is ten times more common in women than men. This difference is due mainly to the fact that the particular anatomy of the female urethra favors infection by the body's own bacterial intestinal flora. The main diagnostic criterion of urinary tract infections is bacteriuria, the presence of bacteria in the properly collected urine sample (midstream urine). For bacteriuria to be considered diagnostically significant, it has to exceed a concentration of 10.sup.5 bacteria per milliliter of urine. bacteriuria to be considered diagnostically significant, it has to exceed a concentration of 10.sup.5 bacteria per milliliter of urine.
Bacteria that reach the urinary tract establish infection either through the bloodstream or by ascending from the urethra to the bladder and then up the ureter to the kidneys. Ascending infection is the most common mode and explains the more frequent occurrence in women. The position of the urethral ostium and the short urethra in women favor infection. Various bacteria originating from the fecal flora are always resident in the urethral ostium and in the distal part of the female urethra. Urinary tract infections in women is initiated when one of the Enterobacteriaceae derived from the fecal flora colonizes in the vaginal vestibule.
The most frequent and abundant constituent of the fecal flora is Escherichia coli, which is also frequently found in the urine as the causative organism in urinary tract infections. Escherichia coli is also usually found in the periurethral region. This bacterium is capable of adhering to the periurcthral epithelial cells. Bacterial adherence is the precondition for the colonization and infection of the urinary tract. Many in-vitro studies have shown that the adherence phenomenon is due to the possession of pili by Escherichia coli that infect the urinary tract. Escherichia coli bacteria are the most frequent causative agents of urinary tract infections.
The urinary tract can also be colonized by other Enterobacteria, such as Proteus and Klebsiella, and gram positive cocci such as Staphylococcus and Streptococcus faecalis (Enterococcus). Other bacteria such as Pseudomonas aeruginesa and Haemophilus influenzae may also invade the urinary tract. Any of the bacterial inhabitants of the intestinal tract that are eliminated in the feces may populate the urinary tracts. Further, the human urinary tract can be colonized by mycoplasma, L-forms of bacteria, Chlamydia, fungi, viruses, and protozoa.
Recurrence and chronicity are characteristic of urinary tract infections. Recurrence may be due to either relapse or reinfection. In spite of a great deal of progress in the treatment of other bacterial infections, the morbidity and mortality of urinary tract infections's remains unchanged in the last 20 to 25 years. The reasons for this are myriad and depend on the host organism and on microbial factors.
Recurrences of infections with a previously infecting organism strain are rare and may result from incorrect choice of medicine, emergence of resistance strains, insufficient treatment duration, insufficient concentration of antibacterial agents, the existence of bacterial L-forms, and survival of organisms in urinary calculi. Recurrent urinary tract infections in women are essentially all reinfections with different organisms and generally with strains having a greater capacity to adhere to the epithelial cells of the vagina and urethra. The reinfecting bacteria originate in the intestinal flora. The composition of the intestinal flora may be altered by prophylactic and therapeutic use of antibiotics and other antibacterial materials which are used in the treatment and prophylaxis of urinary tract infections. The intestinal flora frequently develop antibiotic resistance and the resistant bacteria may then cause a reinfection or primary opportunistic infection of the urinary tract. Such primary infections may be due to opportunistic germs that result from the normal, harmless flora, such as lactobaelli, being wiped out by antibiotics. Other microbes, resistant to the antibiotics, can now flourish and become pathogenic. The bacterial antibiotic resistance caused by R-plasmids is not only transferred between the same species of bacteria, but is also transmitted to almost all Enterobacteriaceae. Multiresistance is also common.
The main cause of recurrent urinary tract infections in women is an immunological defect which facilitates the adhesion of uropathogenic organisms to the periurethral region. Studies have revealed that low levels of urine secretory IgA (sIgA) in urine indicate a defective local immune response of the urinary tract and favor recurrent ascending urinary tract infections. The most important property of sIgA is that they prevent the interaction of bacterial pili with the specific receptors found on the epithelia of the urinary tract. Pili-mediated adhesiveness is an important virulence factor of the bacterial involved. For the defense against infection it is important to reduce the adhesion of the pathogens to the urothelium or to prevent the attachment of the bacteria altogether.
Normally, the host organism forms specific local antibodies against the invading bacteria and secretes these antibodies as sIgA. In patients with persisting or frequently relapsing urinary tract infections this natural mechanism of local immunological infection defense is apparently disturbed. Therefore, enhancement of immune defense is a rational means of eliminating the cause of recurrent urinary tract infections. A vaccination which stimulates the production of antibodies to a spectrum of antigens that are present in several types of Escherichia coli and other commonly occurring urinary bacteria is particularly appropriate.
Previously, urinary tract infections vaccines have been administered parenterally or orally and have resulted in enhanced resistance to urinary tract infections. Parenteral administration of SOLCOUROVAC.RTM., a urinary tract infections vaccine manufactured by Solco Basel AG, Basel Switzerland and described in U.S. Pat. No. 4,606,919, the contents of which are incorporated herein in entirety, decreased post-hysterectomy urinary tract infections, reduced the frequency of infections in susceptible women, and increased sIgA. However, some patients suffered from side effects such as malaise, fever, and muscle soreness. An oral vaccine consisting of immunostimulatory fractions extracted from Escherichia coli strains decreased bacteriuria, septic episodes, requirements for antibiotics in spinal cord injury patients, and the incidence of recurrent urinary tract infections in adult women. As with the parenteral administration, many patients suffered from adverse reactions.
In an attempt to overcome the defects associated with parenteral and oral administrations of urinary tract infections vaccine, an intravaginal vaccine against urinary tract infections was proposed. The rationale for administering a urinary tract infections vaccine intravaginally was that there is a mucosal immune system wherein antigens are absorbed through mucosal surfaces and processed by specialized local lymphoid tissues, after which antibodies are secreted onto local mucosal surfaces. As discussed above, in the genitourinary tract, temporary or partial deficiencies in local vaginal or urinary antibodies are an important factor in the heightened susceptibility to urinary tract infections shown in some women. Immunization via the mucosal surfaces within the genitourinary tract are preferable to parental or oral routes as it has been discovered that vaccination via the intravaginal surface creates a secretory immune response in the urogenital tract.
In the past, urinary tract infections vaccines were administered vaginally in the form of a liquid vaccine. Several problems were associated with the intravaginal administration of liquid urinary tract infections vaccine. The major problem encountered was that the liquid vaccine flowed out of the vagina soon after insertion. This severely limits the amount of time that the liquid antigens are in contact with the mucosal surface of the vagina, decreasing the effectiveness of the vaccine. The antigens need sufficient contact with the vaginal mucous membrane to elicit a secretory immunoglobin response. Patients receiving the vaccination were required to lie in a supine position for an extended time after receiving the vaccine to prevent the vaccine from immediately flowing out of the vagina. However, often the vaccine still leaked out of the vagina following the period of time in the supine position, limiting the effectiveness of the vaccine.
In addition, thc requirement that patients lie in a supine position for an extended time after receiving the vaccine, is a burden on the patient. Patients may receive several vaccinations over the course of treatment and the patients must spend a considerable amount of time after each vaccination immobile. Therefore, it is apparent that improvements are necessary in the prophylaxis against urogenital infectious diseases, such as urinary tract infections, and urinary tract infection vaccines.
The subject invention overcomes the above limitations and others, and teaches a suppository-based vaccine delivery system for prophylaxis against urogenital infectious diseases, such as urinary tract infections.